3-Alkyl-4-sulfamoyl-aniline compounds

ABSTRACT

New 3-alkyl-4-sulfamoyl-aniline compounds of the formula   D R A W I N G

United States Patent [191 Lerch et al.

[451 Oct. 21, 1975 3-ALKYL-4-SULFAMOYL-ANILINE COMPOUNDS [75] Inventors:Ansgar Lerch, Kirrlach; Alfred Popelak, Rimbach; Kurt Stach,Mannheim-Waldhof; Egon Roesch, Lampertheim; Klaus Hardebeck,Ludwigshafen (Rhine), all of Germany [73] Assignee: Boehringer MannheimGmbH,

Mannheim, Germany [22] Filed: June 18, 1973 [21] Appl.No.: 371,212

[30] Foreign Application Priority Data July 1, 1972 Germany 2232457 [52]US. Cl. 260/239.6; 260/239.65; 260/23919; 260/397.7 R; 424/228; 424/229[51] Int. Cl. ..C07D 257/04; CO7D 143/80;v

C07D 307/52: C07D 307/54 [58] Field of Search 260/3977, 239.6, 239.9,260/239.65

[56] References Cited UNITED STATES PATENTS 10/1959 NOVeIIO 260/397.73,565,920 2/I97l Werner 260/3472 3,665,002 5/1972 Popelak et al.260/2399 FOREIGN PATENTS OR APPLICATIONS 2,034,986 l/l972 Germany12/1962 Canada 8/1969 Germany OTHER PUBLICATIONS Siedel, et al., Chem.Ber., 99 (1), 345-352 (1966).

Primary ExaminerMilestone, Norma S. Assistant Examiner-C. M. S. JaisleAttorney, Agent, or FirmBurgess, Dinklage & Sprung [5 7 ABSTRACT New3-alkyl-4-sulfamoyl-aniline compounds of the formula 15 Claims, NoDrawings 3'ALKYL-4-SULFAMOYL-ANILINE COMPOUNDS wherein R, is phenyl,furyl or thienyl;

R is carboxyl or tetrazolyl-() R is a straight-chain or branched alkylradical of from 2 to 5 carbon atoms; and

n is 1 or 2; and the pharmacologically compatible salts thereof.-

In German Pat. No. 2,034,986, there are described4-sulfamoyl-m-toluidine derivatives of general formula (I) in which R,is a methyl radical. These compounds possess diuretic and salureticproperties.

We have now found that by replacement of the methyl radical by a higheralkyl radical, very good saluretic compounds are obtained, some of whichare substantially more effective than the known compounds whenadministered enterally.

The new compounds according to the present invention can be prepared,for example by one of the following methods a. reaction of a compound ofthe general formula:

with an amine of the general formula:

H,N-(CH,),, R, (Ill) wherein R, and n have the same meanings as above;or b. reaction of a compound of the general formula wherein R R, and Yhave the same meanings as above, with a compound of the general formula:

wherein R, and n have the same meanings as above and Z is a reactiveester group, or with a compound of the general formula:

0CH( H2),..Ri (Vl) wherein R, has the same meaning above and m is 0 or1, and optionally hydrogenates simultaneously or subsequently, when R,,is a group which can be converted into a carboxyl group or into atetrazolyl-(5) radical, this is converted into the substituent R 'and,when Y is an acyl radical, this is split off in known manner, whereuponthe compound obtained is, if desired, converted into a pharmacologicallycompatible salt.

Substituents which can be converted into a carboxyl group include, forexample, esterified carboxyl groups and carboxamido and nitrile groups,as well as carboxyl groups in the form of salts with inorganic andorganic bases. Preferred groups which can be converted into thetetrazolyl-(5) radical include nitrile, imido ester and amidine groups.

Compounds V with a reactive ester group 2 include halides, thequaternary addition compound thereof, for example with pyridine, andsulfonic acid esters which can easily be split off, for exampletosylates and brosylates.

The starting materials of general formula (II) are advantageouslyobtained by the sulfochlorination of, for example, 4alkyl-2-br'omobenzoic acids or of their derivatives, with chlorosulfonicacid and subsequent reaction with ammonia.

The starting materials of general formula (IV) can be obtained, forexample, by sulfoamidation of 4-alkyl-2- nitrobenzoic acids or of theirderivatives and subsequent reduction. The corresponding tetrazolylcompounds can be prepared by the reduction of the nitriles with azides.

The process according to the present invention can be carried out at atemperature between 60 l and C, advantageously with the use of an excessof the basic reaction component simultaneously serving to take up theacid liberated by the reaction. For this purpose, there can, however,also be used other inorganic or organic bases or basically reactingcompounds; as examples thereof, mention may be made of alkali metalcarbonates, calcium oxide, triethylamine, dimethylaniline and pyridine.The reaction can be carried out with or without the use of an inertsolvent or diluent, aromatic hydrocarbons, ethylene glycol, ethyleneglycol monomethyl ether, diethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide having proved to be useful for thispurpose. In the case of reactions using inexpensive halides of generalformula (V), these can themselves be used as solvents.

The reaction of the primary amines of general formula (IV) with carbonylcompounds of general formula (VI) gives the corresponding Schiff baseswhich are subsequently reduced in known manner either cata lytically inan inert solvent or with reducing agents, for example, sodiumboro-hydride.

When R is an esterified carboxyl group or a carboxamido or nitrilegroup, these can subsequently be converted into a carboxyl group byhydrolysis, preferably in an alkaline medium.

When it is desired to obtain compounds of general formula (I) in which Ris a tetrazolyl-(5) group, the corresponding compounds in which R, is anitrile, imido ester or amidine group can be reacted with hydrazoic acidor, preferably, with a salt thereof. The reaction can be carried out inan inert solvent, preferably in dimethyl formamide.

The splitting off of an acyl radical Y can be carried out by alkalinesaponification. preferably with an aqueous solution of an alkali metalhydroxide.

The crude products ofgeneral formula (I) can be purified by dissolvingin an aqueous solution of an alkali metal hydroxide and subsequentprecipitating them again with a dilute mineral acid.

If desired, the products obtained can be converted into thecorresponding salts by reaction with inorganic or organic bases.Preferred physiologically compatible salts include the alkali metal,alkaline earth metal and ammonium salts, which can be prepared, forexample, by reaction with an aqueous solution of sodium hydroxide,potassium hydroxide, ammonia or a corresponding carbonate.

The following Examples are given for the purpose of illustrating thepreparation of the compounds of the present invention:

EXAMPLE 1 Preparation of 4-Ethyl-2-furfurylamino-5-sulfamoylbenzoic acid10 g. 4-ethyl-2-bromo-5-sulfamoy1benzoic acid were heated for 12 hoursat 140C. with 30 ml. furfurylamine. After cooling, the reaction mixturewas mixed with 100 ml. 2N aqueous sodium hydroxide solution and thenextracted with ether. The aqueous phase was treated with activecharcoal, filtered and the filtrate was acidified with hydrochloricacid. The crude product which separates out in crystalline form, wasfiltered off with suction and recrystallized from dilute ethanol. Therewere obtained 6.5 g. (62% of theory) 4-ethyl-2-furfurylamino-5-sulfamoylbenzoic acid in the form of colorless crystalswhich melted at 228C.

The following compounds were prepared in an analogous manner:

4-ethyl-2-thenylamino-5-sulfamoylbenzoic acid from4-ethy1-2-bromo-5-su1famoylbenzoic acid and thenylamine; yield 68% oftheory; m.p. 227-228C., after recrystallization from ethanol; For thepreparation of the sodium salt, 2 g. of the product were dissolved, withwarming, in 5 ml. 2N aqueous sodium carbonate solution. Upon cooling,the sodium salt crystallizes out. It has a melting point of 227C.

3-ethyl-4-sulfamoyl-6-tetrazolyl-( 5 )-N- furfurylaniline from3-ethyl-4-su1famoyl-6- tetrazolyl-(S)-1-bromobenzene and furfurylamine;yield 65% of theory; m.p. 179180C., after recrystallization fromethanol;

3-ethy1-4-sulfamoyl-6-tetrazolyl-(5 )-N-benzylaniline from3-ethyl-4-sulfamoy1-6-tetrazolyl-( 5 l bromobenzene and benzylamine;yield 71% of theory; m.p. 237239C., after recrystallization fromacetone/ethanol;

4-isopropyl-2-benzylamino-5-sulfamoy1benzoic acid from4-isopropyl-2-bromo-5-su1famoy1benzoic acid and benzylamine; yield 59%of theory; m.p. 233234C., after recrystallization from methanol/water;

4-isopropyl-2-furfury1amino-5-sulfamoy1benzoic acid from4-isopropyl-2-bromo-5-sulfamoylbenzoic acid and furfurylamine; yield 54%of theory; m.p. l80-l82C. (decmp.), after recrystallization frommethanol/water;

4 4'isopropy1-2-thenylamino-5-sulfamoylbenzoic acid from4-isopropyl-2-bromo-5-sulfamoylbenzoic acid and thenylamine; yield 567:of theory; m.p. 194197C. (decomp). after recrystallization frommethanol/water; 4-buty1-2-furfurylamino-5-su1famoylbenzoic acid from4-butyl-2-bromo-5-sulfamoylbenzoic acid and furfurylamine; yield 72% oftheory; m.p. 239240C., after recrystallization from acetone/ethanol;4buty12-(Z-furylethylamino)-5-sulfamoylbenzoic acid from4-butyl-2-bromo-5-sulfamoylbenzoic acid and 2-fury1ethy1amine; yield 72%of theory; m.p. 227228C., after recrystallization from acetone/ethanol;4-butyl-2-thenylamino-5-sulfamoylbenzoic acid from4-butyl-2-bromo5-sulfamoylbenzoic acid and thenylamine; yield 64% oftheory; m.p. 229230C., after recrystallization from acetone/ethanol;

3-ethyl-4-sulfamoyl-6-tetrazolyl-( 5 )-N-thenylani1ine from3-ethyl-4-sulfamoyl-6-tetrazolyl-( 5 l bromobenzene and thenylamine;yield 79% of the- I cry; m.p. 196198C., after recrystallization fromethanol/water; 3-isopropyl-4-sulfamoyl-6-tetrazolyl-( 5 )-N-thenylaniline from 3-isopropy1-4-su1famoy1-6-tetrazolyl-(S)-1-bromobenzene and thenylamine; yield 52% of theory; m.p.l94195C. (decomp.), after recrystallization from ethyl acetate. Thestarting materials used can be prepared according to the followinggeneral methods: a. 4-alky1-2-bromobenzonitrile l Mole4-alkyl-2-bromo-aniline was diazotized with sodium nitrate at 0-5C. in asolution of sulfuric acid. The clear, ice-cooled diazonium salt solutionwas then added dropwise to a solution of copper cyanide at C., thissolution having been prepared from 1.5 mole crystalline copper sulfateand 6 mole sodium cyanide. The reaction mixture was stirred for 2 hoursat 60C. and thereafter left to stand overnight. The brown precipitatewas then filtered off with suction and immediately subjected to steamdistillation. The distillate was extracted with methylene chloride andthe combined methylene chloride extracts were then washed with a 1Naqueous sodium hydroxide solution and finally with water and then dried.The residue remaining after removal of the solvent is fractionallydistilled in a vacuum. The compounds set out in the following Table144C./3.5 mm.Hg.

b. 4-alky1-2-bromoben zoic acid 50 g. 4-alkyl-2-bromobenzonitrile wereheated with a mixture of 130 ml. concentrated sulfuric acid and 40 ml.water for 1 hour at 130C. Thereafter, a further 100 ml. water were addedthereto and the reaction mixture was heated for 2 hours at C. Afterleaving to cool ,the reaction rnixture was poured into icewater and theTABLE 11 alkyl radical melting point C2H5 s9 91C.

(recrystallised from ligroin) ism-C 11 70 72C.

n-C H 73C.

(recrystallised from ligroin) c. 4-alkyl2-bromo-5-sulfamoylbenzoic acid50 g. 4-alkyl-2-bromobenzoic acid, together with 150 ml. chlorosulfonicacid, were heated for 2 hours at 100C. After cooling, the reactionmixture was poured on to ice and the precipitated sulfochloride wasfiltered off with suction. The still moist material was introduced at20C. into 500 ml. concentrated aqueous ammonium hydroxide solution andleft to stand overnight. The clear solution was then treated with activecharcoal, filtered and the filtrate concentrated somewhat in a vacuum inorder to remove the main amount of ammonia. The concentrate was nowacidified with hydrochloric acidand the precipitated crude product wasfiltered off with suction and then recrystallized from dilute alcohol.The compounds set out in the following Table 111 can be prepared in thismanner:

d. 3-alkyl-6-tetrazolyl-(5 )-bromobenzene 0.1 mole4-alkyl-2-bromobenzonitrile was dissolved in 200 ml. dimethyl formamide,20 ml. water, 0.12 mole sodium azide and 0.12 mole ammonium chloridewere added thereto and the reaction mixture was then heated, whilestirring, for hours at 100C. Subsequently, the solvent was distilled offin a vacuum and the residue was taken up in IN aqueous sodium hydroxidesolution. This solution was extracted with methylene chloride, treatedwith charcoal, filtered and the filtrate acidified with glacial aceticacid. The precipitated crude product was filtered off with suction anddried. The compounds set out in the following Table IV can be preparedin this manner:

e. 3-alkyl-4-sulfamoyl-6-tetrazolyl-(5)-bromobenzene3-Alkyl-6-tetrazolyl-(5)-bromobenzene was sulfochlorinated with thetwofold amount by weight of chlorosulfonic acid. When the reaction wasfinished, the reaction mixture was poured on to ice and the precipitatedsulfochloride was filtered off with suction. While still moist, this wasintroduced at 20C. into a concentrated aqueous solution of ammoniumhydroxide and left to stand overnight. The clear solution was treatedwith:active charcoal, filtered and the filtrate concentrated somewhat ina vacuum. The concentrated was then acidified with hydrochloric acid andthe crude product obtained was filtered offwith suction and thenrecrystallized from methanol/water. The compounds set out in thefollowing Table V can be prepared in this manner:

For use as pharmaceuticals with a diuretic and natriuretic action, thenew compounds according to the present invention can, in principle, beused in all the conventional enteral and parenteral forms ofadministration. For this purpose, the active materials were mixed withsolid or liquid pharmaceutical diluents or carriers and then broughtinto a suitable form.

Examples of solid carrier materials include lactose, mannitol, starch,talc, methyl cellulose, gelatine and the like, to which, if desired, canbe added coloring materials and/or flavorings. Because of the lowsolubility of the compounds according to the present invention, forinjectable solutions very few solvents can be used, for example dimethylsulfoxide. Higher concentrations are, therefore, preferably administeredin the form of suspensions. In human medicine, in the case of enteraladministration, doses of active materials of between 10 and 500 mg. perday in 1 to 4 individual doses have proved to be useful; in the case ofintravenous administration, the most favorable dosage range is between 5and mg. per day.

The new compounds according to the present invention have a strong,rapidly commencing diuretic action. Simultaneously with the increasedexcretion of water, an increased amount of sodiums is also excreted. Theincreased excretion of potassium ions, which occurs simultaneously inthe case of comparable known substances, is, in the case of thecompounds according to the present invention, considerably lower. Inthis way, higher sodium-potassium quotients are obtained, i.e., the newcompounds according to the present invention enable the physician tobring about in his patients a rapid, sudden and considerably increasedexcretion of water and of sodium ions without, at the same time,substantially influencing the potassium balance.

The compounds of this invention possess outstanding saluretic propertiesas well. In order to establish the effectiveness of compoundsrepresentative of this invention as therapeutic agents for diuretic andsaluretic purposes, the following series of tests were .carried out.

The test animals were female Sprague-Dawley rats each weighing between-200 grams. The rats were kept in climate controlled rooms at 23 i 1Cand a rel- 5 ative humidity of 60 i 5% for at least one week prior tothe tests. On the evening prior to the test day (i.e., 16 hours prior toadministration of test compounds),

the test rats were left without food and had access only to drinkingwater. During the tests, groups of animals were placed into metaboliccages and such groups of animals were used in the tests. The testcompounds were administered to the testanimals as a suspension in tyloseat the rate of milliliters per kg of body weight of each rat. The testpreparations were injected intraperitoneally or administered orally. Thedosage in terms of milligrams of test compounds per kg of body weight isset forth in the Table below. Prior to the test and after 2 hours andagain after 6 hours subsequent to the test, the bladders of the ratswere emptied by squeezing, the urine content was measured, sodium andpotassium were determined by flame photometric tests.

The following were the test compounds: (The numbered compounds below arerepresentative of the invention; the lettered compounds, i.e., compoundsA, B, C and D are the S-methyl analogs of the representative compoundsof the instant invention and are included for purposes of comparison.)

Compound No.

A 4-Sulfamoyl-6carboxyN-thcnylm-toluidinc 14-Ethyl-2-thcnylamino-5-sulfumoy1 bcnzoic acid B4-Sulfamoyl-6-tetrazolyl(5l-N- N-bcnzylanilinc 34-lsopropyl-2-hcnzylamino-5-sulfamoylbcnzoic acid4-Su1famoy1-6-tctrazolyl(5l-N- thcnyl-m-toluidinc3-lsopropyl-4-sulfamoyl-6-tctruzolyl(5 N-thcnylanilinc4-1sopropyl2-thcnylamino S-suIfamoyl bcnzoic acid un'bu wherein R, isphenyl. furyl or thienyl;

R is carboxyl or tetrazolyl-(S);

R is a straight-chain or branched alkyl radical of from 2 to 5 carbonatoms;

n is 1 or 2; or

a pharmacologically compatible salt thereof.

2. 3-A]kyl-4-sulfamoyl-aniline compound as claimed in claim 1, whereinR, is phenyl.

3. 3-A1kyl-4-sulfamoyl-aniline compound as claimed in claim 1, whereinR, is furyl.

4. 3-Alkyl-4-su1famoyl-aniline compound as claimed in claim 1, whereinR, is thienyl.

5. 3-A1ky1-4-sulfamoyl-aniline compound as claimed in claim 1, wherein Ris carboxyl.

6. 3-A1ky1-4-sulfamoyl-aniline compound as claimed in claim 1, wherein Ris tetrazolyl-(S).

7. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, wherein Ris ethyl.

8. 3-A1kyl-4-sulfamoyl-aniline compound as claimed in claim 1, wherein Ris propyl.

9. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, wherein Ris butyl.

l0. 3-A1ky1-4-sulfamoyl-aniline compound as claimed in claim 1, whereinR is pentyl.

ll. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1,designated 4-ethyl-2-thenylamino- 5-sulfamoylbenzoic acid.

12. 3-A1kyl-4-sulfamoyl-ani1ine compound as claimed in claim 1,designated 3-ethyl-4-sulfamoyl-6- tetrazolyl(5)-N-benzylaniline.

13. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1,designated 4-isopropyl 2- Diuretic and Saluretic Properties ofIllustrating Compounds Relative to S-Mcthyl Counterparts Thereof (Ureaand Salt Excretion in Rats) Separation/kg During Test Compound DosageTwo Hours Six Hours Na mgl kg ml urine Na K K ml urine Na K K Controli.p. i.p. 6 0.05 0.22 0.3 9 0.17 0.56 0.3 A 50 47 4.7 1.1 4.1 53 5.0 1.92.7 1 50 36 4.5 0.84 5.3 4.7 1.3 3.5 B 43 4.6 1.2 3.8 54 5.4 2.0 2.8 25O 42 4.9 0.90 5.5 52 5.9 1.7 3.4 C 50 38 4.4 1.1 4.1 42 4.5 1.6 2.8 350 29 3.3 0.56 5.9 30 3.4 0.82 4.1 Control p o p.o. 9 0.10 0.22 0.5 130.43 0.62 0.7 D 25 10 0.28 0.20 1.4 25 2.1 1.0 2.1 4 25 9 0.19 0.25 0.734 2.8 1.2 2.2 A 50 24 1.4 0.75 1.9 35 2.7 1.5 1.5 5 5O 41 3.4 0.97 3.643 3.6 1.3 2.8

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

What is claimed is:

l. A 3-alkyl4-sulfamoyl-aniline compound of the formula:

benzy1amino-5-sulfamoylbenzoic acid.

14. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1,designated 4-isopropyl-2- thenylamino-S-sulfamoyl benzoic acid.

15. 3-A1kyl-4-sulfamoyl-aniline compound as claimed in claim 1,designated 3-isopropyl-4-sulfamoyl- 6-tetrazolyl(5 )-N-thenylaniline.

1. A 3-ALKYL4-SULFAMOYL-ANILINE COMPOUND OF THE FORMULA: 2.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, wherein R1is phenyl.
 3. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim1, wherein R1 is furyl.
 4. 3-Alkyl-4-sulfamoyl-aniline compound asclaimed in claim 1, wherein R1 is thienyl. 5.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, wherein R2is carboxyl.
 6. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim1, wherein R2 is tetrazolyl-(5).
 7. 3-Alkyl-4-sulfamoyl-aniline compoundas claimed in claim 1, wherein R4 is ethyl. 8.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, wherein R4is propyl.
 9. 3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim1, wherein R4 is butyl.
 10. 3-Alkyl-4-sulfamoyl-aniline compound asclaimed in claim 1, wherein R4 is pentyl. 11.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, designated4-ethyl-2-thenylamino-5-sulfamoylbenzoic acid. 12.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, designated3-ethyl-4-sulfamoyl-6-tetrazolyl(5)-N-benzylaniline. 13.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, designated4-isopropyl-2-benzylamino-5-sulfamoylbenzoic acid. 14.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, designated4-isopropyl-2-thenylamino-5-sulfamoyl benzoic acid. 15.3-Alkyl-4-sulfamoyl-aniline compound as claimed in claim 1, designated3-isopropyl-4-sulfamoyl-6-tetrazolyl(5)-N-thenylaniline.